PROJECT SUMMARY Non-invasive stimulation of the cerebellum holds great promise for investigating brain function, and for diagnosing and treating a variety of brain disorders. Given the classical role of the cerebellum in motor control, it is not surprising that many studies have reported that cerebellar transcranial direct current stimulation (CB- tDCS) can be used to enhance motor function and mitigate the symptoms of ataxia, dystonia and essential tremor. More recent studies have shown that CB-tDCS can modulate cognitive function as well, including working memory and emotional processing. Despite the great success that CB-tDCS has enjoyed in the last 15 years, we know very little about the way it works. The goal of this proposal is to fill this gap in knowledge by measuring for the first time the impact that CB-tDCS has on the activity of neurons in different regions of the brain. Mice will be used, and the polarity (anodal or cathodal) and the intensity of the stimulation will be systematically varied to determine the dose/response relationship between CB-tDCS and neural activity. To help translate the results to the human brain, the stimulation doses will be comparable to those that have been applied in clinical studies. In addition, the responses of neurons to CB-tDCS will be examined under different physiological states, including during rest as well as during sensory processing and motor performance. The experiments will take advantage of powerful genetic strategies to target specific neural populations, and to manipulate and record their activity with an unprecedented level of spatial and temporal resolution. The general plan is to start by assessing the local effects of CB-tDCS in the cerebellar cortex, and gradually move downstream, first to neurons in the deep cerebellar nucleus, and then to other regions of the brain that are connected to the cerebellum. The results of these experiments will provide critical information to help optimize the use of CB-tDCS for neuroscience research as well as for clinical application.